不同力场对B-DNA到A-DNA构型转变的影响

doi:10.7503/cjcu20180201

摘要/Abstract

摘要：

采用分子动力学模拟方法比较了最新版CHARMM和AMBER(包括bsc1和OL15)力场对水溶液中B-DNA到A-DNA转化过程的影响, 利用扩展自适应偏置力(eABF)方法计算了转化过程的自由能变化. 研究结果表明, 在不同力场下, 水环境中的DNA最稳定结构存在差异, AMBER力场比CHARMM力场更符合实验结果. AMBER力场下DNA最稳定结构的小沟较窄, 稳定于B构型; 而CHARMM力场下DNA最稳定结构的小沟较宽, 介于B构型与A构型之间. 通过分析DNA周围离子及水的分布情况发现, CHARMM力场下DNA小沟周围的离子密度明显低于AMBER力场, 不能很好地抵消2条磷酸骨架之间的排斥作用, 这是CHARMM力场下小沟较宽且趋向A构型的主要原因.

关键词: B-DNA, A-DNA, 构型转变, CHARMM力场, AMBER力场, 自由能计算

Abstract:

The aim of the present work is to investigate and compare the effect of the latest CHARMM and AMBER force fields(including bsc1 and OL15) on the B-DNA to A-DNA conversion through exploring the free-energy changes of the conversion process. The extended adaptive biasing force(eABF) method was utilized to perform the free-energy calculations. The results showed that the free-energy profiles characterizing the transition differ significantly for these two force fields. The AMBER force field performs better than the CHARMM force field in aqueous solution. The structure near the global minimum of the free-energy profile by the AMBER force field presents B-form, in agreement with the experimental results, while the most stable structure by the CHARMM force field locates between A- and B-form. Deep analysis of the radial distribution functions of the counterions around DNA reveals that the distribution of counterions in minor groove using the CHARMM force field is lower than that using the AMBER force field. Therefore, for the CHARMM force field, the repulsion of phosphates backbone could not be properly counteracted by counterions, as a result, the minor groove becomes wider, causing a slight conformational change towards A-form.

Key words: B-DNA, A-DNA, Conformational conversion, CHARMM force field, AMBER force field, Free-energy calculation

中图分类号:

O641

TrendMD:

张宏, 蔡文生, 邵学广. 不同力场对B-DNA到A-DNA构型转变的影响. 高等学校化学学报, 2018, 39(6): 1205.

ZHANG Hong, CAI Wensheng, SHAO Xueguang. Effect of Different Force Fields on B-DNA to A-DNA Conversion^†. Chem. J. Chinese Universities, 2018, 39(6): 1205.

图/表 10

Fig.1 Structures of canonical A-DNA(A) and canonical B-DNA(B)

Fig.2 Free-energy profiles characterizing the B-DNA to A-DNA conversion for the hexamer sequence(AT)6(A) and (GC)6(B)ΔRMSD=-0.3 nm, 0.3 nm denotes an ideal B-DNA, and ideal A-DNA, respectively. a. AMBER-bsc1 force field; b. CHARMM force field; c. AMBER-OL15 force field.

Fig.3 Selected structures near the global minimum of the PMFs for the hexamer sequence (AT)6 (A) AMBER-bsc1 force field; (B) CHARMM force field; (C) AMBER-OL15 force field.

Fig.4 Selected structures near the global minimum of the PMFs for the hexamer sequence (GC)6 (A) AMBER-bsc1 force field; (B) CHARMM force field; (C) AMBER-OL15 force field.

Fig.5 Populations of major-groove widths computed over the 10 ns equilibrium simulation(A) (AT)6; (B) (GC)6. a. bsc1; b. CHARMM; c. X-ray. Properties of crystal structure were computed from the inner six base pairs of PDB code 4J2I and 1QC1.

Fig.6 Populations of minor-groove widths computed over the 10 ns equilibrium simulation(A) (AT)6; (B)(GC)6. a. bsc1; b. CHARMM; c. X-ray. Properties of crystal structure were computed from the inner six base pairs of PDB code 4J2I and 1QC1.

Fig.7 K+/backbone RDF(A), K+/major-groove RDF(B) and K+/minor-groove RDF(C) computed over the 10 ns equilibrium simulation for (GC)6 sequencea. bsc1; b. CHARMM.

Fig.8 K+/backbone RDF(A), K+/major-groove RDF(B) and K+/minor-groove RDF(C) computed over the 10 ns equilibrium simulation for (AT)6 sequence a. bsc1; b. CHARMM.

Fig.9 Water/backbone RDF(A), water/major-groove RDF(B) and water/minor-groove RDF(C) computed over the 10 ns equilibrium simulation for (GC)6 sequence a. bsc1; b. CHARMM.

Fig.10 Water/backbone RDF(A), water/major-groove RDF(B) and water/minor-groove RDF(C) computed over the 10 ns equilibrium simulation for (AT)6 sequence a. bsc1; b. CHARMM.

参考文献 27

[1]	Saenger W., Defining Terms for the Nucleic Acid., Springer, New York, 1984
[2]	Ivanov V. I., Minchenkova L. E., Minyat E. E., Frank-Kamenetskii M. D., Schyolkina A. K., J. Mol. Biol., 1974, 87(4), 817—833
[3]	Mukherjee A., Lavery R., Bagchi B., Hynes J. T., J. Am. Chem. Soc., 2008, 130(30), 9747—9755
[4]	Dumont E., Wibowo M., Roca-Sanjuán D., Garavelli M., Assfeld X., Monari A., J. Phys. Chem. Lett., 2015, 6(4), 576—580
[5]	Foloppe N., MacKerell A. D. Jr., J. Comput. Chem., 2000, 21(2), 86—104
[6]	MacKerell A. D. Jr., Bashford D., Bellott M., Dunbrack R. L. Jr., Evanseck J. D., Field M. J., Fischer S., Gao J., Guo H., Ha S., J. Phys.Chem. B, 1998, 102(18), 3586—3616
[7]	Ivani I., Dans P. D., Noy A., Pérez A., Faustino I., Hospital A., Walther J., Andrio P., Goñi R., Balaceanu A., Nat. Methods, 2016, 13(1), 55
[8]	Zgarbová M., Luque F. J., Šponer J. I., Cheatham III T. E., Otyepka M., Jurecka P., J. Chem. Theory Comput., 2013, 9(5), 2339—2354
[9]	Soares T. A., Hünenberger P. H., Kastenholz M. A., Kräutler V., Lenz T., Lins R. D., Oostenbrink C., van Gunsteren W. F., J. Comput. Chem., 2005, 26(7), 725—737
[10]	Robertson M. J., Tirado-Rives J., Jorgensen W. L., J. Chem. Theory Comput., 2015, 11(7), 3499—3509
[11]	Song C., Xia Y. Y., Zhao M. W., Liu X. D., Li F., Ji Y. J., Huang B. D., Yin Y. Y., J. Mol. Model., 2006, 12(3), 249—254
[12]	Cheatham T. E., Crowley M. F., Fox T., Kollman P. A., Proc. Natl. Acad. Sci. USA, 1997, 94(18), 9626—9630
[13]	Yang L., Pettitt B. M., J. Phys. Chem., 1996, 100(7), 2564—2566
[14]	Shen W., Shao X. G., Cai W. S., Chem. J. Chinese Universities, 2016, 37(10), 1809—1816
	(沈文, 邵学广, 蔡文生. 高等学校化学学报, 2016, 37(10), 1809—1816)
[15]	Fu H. H., Shao X. G., Chipot C., Cai W. S., J. Chem. Theory Comput., 2016, 12(8), 3506—3513
[16]	Acosta-Reyes F. J., Subirana J. A., Pous J., Sánchez-Giraldo R., Condom N., Baldini R., Malinina L., Campos J. L., Biopolymers, 2015, 103(3), 123—133
[17]	Timsit Y., Moras D., EMBO J., 1994, 13(12), 2737
[18]	Phillips J. C., Braun R., Wang W., Gumbart J., Tajkhorshid E., Villa E., Chipot C., Skeel R. D., Kale L., Schulten K., J. Comput. Chem., 2005, 26(16), 1781—1802
[19]	Jorgensen W. L., Chandrasekhar J., Madura J. D., Impey R. W., Klein M. L., J. Chem. Phys., 1983, 79(2), 926—935
[20]	Ryckaert J. P., Ciccotti G., Berendsen H. J., J. Comput. Phys., 1977, 23(3), 327—341
[21]	Andersen H. C., J. Comput. Phys., 1983, 52(1), 24—34
[22]	Miyamoto S., Kollman P. A., J. Comput. Chem., 1992, 13(8), 952—962
[23]	Feller S. E., Zhang Y., Pastor R. W., Brooks B. R., J. Chem. Phys., 1995, 103(11), 4613—4621
[24]	Humphrey W., Dalke A., Schulten K., J. Mol. Graphics, 1996, 14(1), 33—38
[25]	Lavery R., Moakher M., Maddocks J., Petkeviciute D., Zakrzewska K., Nucleic Acids Res., 2009, 37(17), 5917—5929
[26]	Banavali N. K., Roux B., J. Am. Chem. Soc., 2005, 127(18), 6866—6876
[27]	Hamelberg D., Williams L. D., Wilson W. D., J. Am. Chem. Soc., 2001, 123(32), 7745—7755